This project will continue to describe alterations in cerebral blood flow that occur during hyperglycemia and seek to identify the mechanisms involved in the production of these alterations. It is motivated by the observation that although hyperglycemia is associated with specific clinical syndromes of brain dysfunction, and can potentiate brain injury during stroke or cardiac arrest, little is known about its effect on the cerebral circulation. Accordingly, the aim of this proposal is to describe the effects of acute and chronic hyperglycemia on the rat cerebral circulation as it responds to a local pathological insult. The proposal will use the involvement of the rat forebrain by the spreading depression of electrocortical activity induced by cathodal current as a model of the response of the cerebral circulation to local injury. Cortical spreading depression is a common response of the mammalian cerebrum to injury, and may occur in humans during these same conditions. the responses of the cerebral circulation to this pathological event during hyperglycemia will be quantified by measurement of local cerebral blood flow using the diffusible indicator iodoantipyrine and quantitative autoradiography. the relationship between cerebral blood flow and brain metabolism will be determined by measuring the blood-brain barrier permeability to glucose and the cerebral metabolic rate of glucose consumption using glucose-tracer methods. Acute hyperglycemia will be induced using streptozotocin. The work will describe a novel concept in the control of the cerebral circulation; tone-dependent blood flow alterations in the wake of spreading depression. It is hypothesized that spreading depression produces a selective loss of the regulatory function of the microcirculation of the cortex. This selective loss of function of the unmasks the tone-dependent regulation of the pial vessel diameter by vasopressin and, perhaps, dynorphin. During spreading flow. This hypothesis will be tested using receptor antagonists for these compounds. The results of this proposal will provide a framework for the interpretation of measurements of cerebral blood flow obtained during the study of migraine headaches, focal epilepsy, and focal cerebral ischemia.